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Blood. 2014 Jul 17;124(3):453-62. doi: 10.1182/blood-2014-04-567933. Epub 2014 Jun 2.

Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia.

Author information

1
Cancer Vaccine Center and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
2
Cancer Vaccine Center and Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA;
3
Division of Medical Sciences: Biological and Biomedical Sciences, Harvard Medical School, Boston, MA;
4
Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA;
5
La Jolla Institute for Allergy and Immunology, La Jolla, CA;
6
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA;
7
Cancer Vaccine Center and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
8
Cancer Vaccine Center and.
9
Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA; Massachusetts General Hospital Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA; and.
10
Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA; The Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Abstract

Genome sequencing has revealed a large number of shared and personal somatic mutations across human cancers. In principle, any genetic alteration affecting a protein-coding region has the potential to generate mutated peptides that are presented by surface HLA class I proteins that might be recognized by cytotoxic T cells. To test this possibility, we implemented a streamlined approach for the prediction and validation of such neoantigens derived from individual tumors and presented by patient-specific HLA alleles. We applied our computational pipeline to 91 chronic lymphocytic leukemias (CLLs) that underwent whole-exome sequencing (WES). We predicted ∼22 mutated HLA-binding peptides per leukemia (derived from ∼16 missense mutations) and experimentally confirmed HLA binding for ∼55% of such peptides. Two CLL patients that achieved long-term remission following allogeneic hematopoietic stem cell transplantation were monitored for CD8(+) T-cell responses against predicted or confirmed HLA-binding peptides. Long-lived cytotoxic T-cell responses were detected against peptides generated from personal tumor mutations in ALMS1, C6ORF89, and FNDC3B presented on tumor cells. Finally, we applied our computational pipeline to WES data (N = 2488 samples) across 13 different cancer types and estimated dozens to thousands of predicted neoantigens per individual tumor, suggesting that neoantigens are frequent in most tumors.

PMID:
24891321
PMCID:
PMC4102716
DOI:
10.1182/blood-2014-04-567933
[Indexed for MEDLINE]
Free PMC Article
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